Erik K. Alexander

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Associations (ATAs) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Societys Journals Online web site at http://jcem.endojournals.org). EVIDENCE This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society, Asia and Oceania Thyroid Association, and the Latin American Thyroid Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. CONCLUSIONS Practice guidelines are presented for diagnosis and treatment of patients with thyroid-related medical issues just before and during pregnancy and in the postpartum interval. These include evidence-based approaches to assessing the cause of the condition, treating it, and managing hypothyroidism, hyperthyroidism, gestational hyperthyroidism, thyroid autoimmunity, thyroid tumors, iodine nutrition, postpartum thyroiditis, and screening for thyroid disease. Indications and side effects of therapeutic agents used in treatment are also presented.

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

Long-term Assessment of a Multidisciplinary Approach to Thyroid Nodule Diagnostic Evaluation

The diagnostic evaluation of patients with thyroid nodules is imprecise. Despite the benefits of fine‐needle aspiration (FNA), most patients who are referred for surgery because of abnormal cytology prove to have benign disease. Recent technologic and procedural advances suggest that this shortcoming can be mitigated, although few data confirm this benefit in unselected patients.

Hypothyroidism after Sunitinib Treatment for Patients with Gastrointestinal Stromal Tumors

Context Sunitinib, a tyrosine kinase inhibitor, has recently been approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Contribution In a series of imatinib-resistant patients treated with sunitinib for gastrointestinal stromal tumors, 36% developed hypothyroidism during the course of treatment. Incidence of hypothyroidism increased progressively with duration of treatment. Implications Disruption of specific cellular signaling pathways by kinase inhibitors that are intended to interfere with malignant cell growth may have profound and unanticipated metabolic consequences. Patients receiving kinase inhibitors should be closely monitored for the occurrence of adverse effects on other organ systems. The Editors Tyrosine kinase inhibitors are beneficial for the treatment of numerous malignant conditions. Although each small molecule is modeled to block the activity of selected kinase signaling enzymes, it is increasingly evident that many have overlapping effects on several kinase pathways. Sunitinib malate (Sutent [previously known as SU11248], Pfizer, Inc., New York, New York), a multitargeted small-molecule tyrosine kinase inhibitor with proven antitumor activity against gastrointestinal stromal tumors and renal cell carcinoma, has recently been approved in the United States and Europe for treatment of patients with metastatic or surgically unresectable disease (14). Although the drug is usually well tolerated, patient-reported fatigue noted during clinical trials led to the monitoring of serum thyroid-stimulating hormone (TSH) concentrations to rule out primary hypothyroidism. After the identification of 2 index case-patients who developed primary hypothyroidism, we expanded our observations in patients receiving sunitinib therapy to further define this association. Index case-patient 1, a 39-year-old woman, presented with lower gastrointestinal bleeding and was found to have a gastrointestinal stromal tumor of the stomach wall with several liver metastases. Following surgery to resect the bleeding lesion, she was treated with imatinib mesylate. Within months, serial imaging confirmed disease progression. Imatinib was withdrawn, and she enrolled in a phase I/II clinical study investigating the safety and efficacy of sunitinib. She received sunitinib in repeated 4-week cycles (50 mg/d for 2 weeks, followed by a 2-week washout phase). At initiation of therapy, the patient had an Eastern Cooperative Oncology Group performance status of zero and had no cold intolerance, constipation, fatigue, or other signs of hypothyroidism. Baseline serum TSH concentration was 1.6 mU/L (normal range, 0.5 to 5.0 mU/L). The patient was treated with sunitinib for more than 1 year and had normal serum TSH concentration during this time, except 1 value of 8.8 mU/L at 38 weeks of therapy (Figure 1). During the 60th week of sunitinib therapy, she reported progressive fatigue, confusion, and cold intolerance. Physical examination was notable for myxedema. The results of thyroid function testing showed a serum TSH value of 288 mU/L. l-Thyroxine was administered, and a normal TSH value was achieved, resulting in resolution of symptoms. Figure 1. Biochemical findings of thyroid dysfunction in a patient treated with sunitinib for recurrence of gastrointestinal stromal tumor. The figure depicts sequential thyroid-stimulating hormone (TSH) measurements during 2 years of sunitinib therapy. l-Thyroxine therapy was initiated at week 74. At 92 weeks, the patient was referred from the oncology program to the Division of Endocrinology for consultation at the Brigham and Womens Hospital, Boston, Massachusetts. At that time, the patient appeared clinically euthyroid, and results of thyroid function tests were normal while she was receiving 150 g of l-thyroxine per day. Her thyroid was not palpable, and results on neck ultrasonography showed minimal thyroid tissue. Index case-patient 2, a 38-year-old woman, presented with a metastatic gastrointestinal stromal tumor. She had previously been treated with imatinib for 18 months before developing refractory disease. Imatinib was withdrawn, and the patient began receiving sunitinib in repeated 6-week cycles (50 mg/d for 4 weeks, followed by a 2-week washout period) at a different cancer center. After she developed diarrhea and fatigue, her dose was reduced to 37.5 mg/d. Following 24 weeks of sunitinib therapy, she noted heart palpitations, heat intolerance, dysphagia, and anterior neck pain lasting several weeks. After approximately 30 weeks of therapy, the patient developed progressive fatigue, cold intolerance, hoarseness, and constipation. These symptoms were initially attributed to direct effects of sunitinib in conjunction with systemic effects of her tumor. After 51 weeks of sunitinib therapy, she was referred to the Dana Farber Cancer Institute, Boston, Massachusetts, and her persistent symptoms suggesting hypothyroidism prompted an endocrine consultation. She was extremely hypothyroid, with dry skin, nonpitting edema, absence of palpable thyroid tissue, and delayed relaxation of deep tendon reflexes. The results of a neck ultrasonography showed no visible thyroid tissue (Figure 2). Her TSH level was 101 mU/L; serum thyroxine concentration was 21 nmol/L (1.6 g/dL) (normal range, 64 to 142 nmol/L [5 to 11 g/dL]), her thyroid hormone binding ratio was 0.48 (normal range, 0.8 to 1.2), her free thyroxine index was 0.8 (normal range, 5 to 11), and her thyroid peroxidase antibody was 17.6 U/mL (normal range, 0 to 20 U/mL). The patient was treated with l-thyroxine, 88 g/d, resulting in complete resolution of her symptoms. On the basis of these initial findings in 2 patients receiving sunitinib, we sought to prospectively evaluate thyroid function in patients enrolled in a phase I/II study investigating sunitinib as a treatment for patients with imatinib-resistant gastrointestinal stromal tumors at the Dana Farber Cancer Institute. Methods Patients Between April 2002 and December 2004, 79 patients were treated in a phase I/II trial investigating sunitinib therapy for the treatment of imatinib-resistant gastrointestinal stromal tumors. Most received 50 mg of sunitinib per day in repeated 4- or 6-week cycles, each consisting of 2 to 4 weeks of sunitinib followed by 2 weeks with no therapy. Patients enrolled in this study had stopped receiving imatinib therapy at least 14 days before starting sunitinib therapy. Between April 2002 and September 2002, thyroid function tests were performed only if there was a clinical suspicion of hypothyroidism. Beginning in October 2002, the study protocol was modified to include measurements of serum TSH at the beginning of each sunitinib treatment cycle. In December 2004, the Endocrinology Division began collaborative evaluation of this population. Serum TSH values were available for 69 of 79 patients (87%), 20 of whom were excluded from primary analysis because of abnormal thyroid function or l-thyroxine therapy preceding initiation of sunitinib or because baseline data were not available. Of these 20 patients, 8 patients were receiving l-thyroxine therapy at study entry (6 had begun l-thyroxine therapy before either imatinib or sunitinib therapy, and 3 patients were first tested for thyroid function after treatment with 5 cycles of sunitinib; 9 other patients had abnormal baseline thyroid function (7 had elevated TSH concentrations, and 2 had suppressed TSH concentrations). Seven additional patients with normal baseline thyroid function received sunitinib therapy for less than 3 cycles because of progressive disease or drug intolerance and were also excluded. No participants received medications known to cause thyroid dysfunction, such as iodinated compounds, lithium, or interferon. Thus, we evaluated results in 42 patients with normal baseline thyroid function treated with sunitinib for at least 3 cycles. These 42 patients were treated for a median of 37 weeks (range, 10 to 167 weeks). Biochemical Evaluation and Treatment Patients were screened for thyroid dysfunction by monitoring serum TSH concentration (5, 6). A TSH concentration greater than 5.0 mU/L was considered abnormal. Patients with substantial increases in TSH were further evaluated, and treatment with l-thyroxine was initiated as indicated. Role of the Funding Source The phase I/II trial of sunitinib was funded in part by Pfizer, Inc., and the results of the trial have been reported elsewhere. There was no separate industry funding source for this investigation, and funding played no role in the collection, analysis, and interpretation of these data or in the decision to submit this paper for publication. The institutional review board of the Dana Farber Cancer Institute granted permission to perform these investigations. Results During the phase I/II trial of sunitinib, 15 of 42 (36%) patients developed hypothyroidism after an average of 50 weeks of therapy (range, 12 to 94 weeks) (Table). Of these, 9 had TSH concentrations more than 20 mU/L (mean maximal serum TSH concentration, 100 mU/L) and 6 had TSH concentrations between 7.0 and 20 mU/L. Seven additional patients (17%) had at least 1 TSH concentration between 5.0 and 7.0 mU/L while receiving sunitinib that subsequently normalized. Four patients developed TSH suppression while receiving sunitinib but discontinued the study protocol before repeated thyroid function studies could be performed. In summary, abnormal serum TSH values were documented in 26 of 42 (62%) patients receiving sunitinib. Eastern Cooperative Oncology Group functional status was similar in patients with normal thyroid function and in those who were hypothyroid, suggesting that acute illness did not selectively influence thyroid function in affected patients. Table. Serum Thyroid-Stimulating Hormone Concentrations in 15 Patients Who Developed Hypothyroidism during Sunitinib Therapy for the Treatment of Gastrointestinal Stromal Tumors Six of the 15 (40%

Natural History of Benign Solid and Cystic Thyroid Nodules

Context Although benign thyroid nodules are common, we know relatively little about their natural history. Contribution This observational study from a single tertiary care facility used repeated ultrasonography to show that benign thyroid nodules typically increase in volume over a 3- to 5-year period. Solid nodules grew more than cystic nodules, and only 1 of 74 reaspirated nodules was malignant. Implications Nodule growth alone does not predict malignancy. The Editors Thyroid nodules are present in nearly 50% of adults, increasing in prevalence with age (1). The evaluation of thyroid nodules that measure 1 cm or greater in diameter typically includes a screening measure of serum thyroid-stimulating hormone (TSH) levels and fine-needle aspiration (FNA). Most FNA results are benign (90% to 95%), and follow-up examinations are advised. Recommendations include periodic clinical examinations or ultrasonography, with or without suppressive l-thyroxine therapy (1, 2). Nodules that increase in size during follow-up are often regarded as suspicious for malignancy, and repeated FNA or surgery is advised (3-6). Data supporting these recommendations are limited, however, as few reports have evaluated thyroid nodule growth using the most sensitive technique, high-resolution ultrasonography. Furthermore, criteria defining nodule growth are inconsistent; some guidelines use an increase in maximal diameter of greater than 50%, while others suggest an increase in maximal diameter greater than 5 mm or an increase in calculated volume greater than 15% (5-10). We used ultrasonography of thyroid nodules to determine the natural history of cytologically benign thyroid nodules over a 1-month to 5-year follow-up period. Methods We retrospectively reviewed the records of all patients referred to the dual-discipline Thyroid Nodule Clinic at Brigham and Womens Hospital, Boston, Massachusetts, for evaluation of nodular thyroid disease between 1995 and 2000. All patients referred to the clinic underwent ultrasonography of the thyroid by a radiologist and ultrasonography-guided FNA of nodules measuring 1 cm or greater in maximal diameter by an endocrinologist. All ultrasonography evaluations were adequate for review and interpretation. All patients with benign cytology on initial FNA were advised to schedule follow-up ultrasonography 9 to 12 months later. Repeated FNA was performed on the follow-up visit at the discretion of the endocrinologist, usually because of nodule growth. The study sample included all patients with nodules with benign cytologic results on the initial visit who returned for follow-up ultrasonography within the 5-year period. Thyroid ultrasonography was performed by one of three radiologists using a 5- to 15-MHz transducer. The length, width, and depth of each nodule were reported, and each nodule was classified as solid, less than 25% cystic, 25% to 50% cystic, 50% to 75% cystic, or greater than 75% cystic. Nodule volume was calculated by using the formula for a rotational ellipsoid (length width depth /6) (7, 11, 12). Ultrasonography-guided FNA was performed with a 25-gauge needle (three to four aspirations per nodule), and specimens were processed by using the Thin-Prep technique (Cytyc Corp., Boxborough, Massachusetts). All slides were read by a cytopathologist at Brigham and Womens Hospital. Specimens were considered benign when six or more groups of benign follicular cells (each group containing 15 cells) were identified without atypical features. Repeated ultrasonographies were performed, and findings were directly compared with the previous images. Change in nodule size over the interval between examinations was assessed by using three criteria: 1) change in maximal diameter greater than 50% [7, 8, 12, 13]; 2) change in maximal diameter of 3 mm or more; 3) change in calculated volume of 15% or more (11, 14). The latter two criteria are defined by established inaccuracy rates for each method (11, 15). The Investigational Review Board of Brigham and Womens Hospital granted permission to perform this review. Descriptive statistics are presented according to nodule or patient as appropriate. The main outcome for the single-variable and multivariable predictive models was nodule growth, defined as an increase in volume of 15% or greater. Single-variable and multivariable mixed-effects logistic regression was used to predict growth, while accounting for the correlation structure in the data where some patients had more than one nodule (16). Potential predictors were the time between examinations, cystic content (solid, <25% cystic, 25% to 50% cystic, 50% to 75% cystic, or >75% cystic), TSH level (mIU/L), l-thyroxine use, age, and sex. Unadjusted and adjusted odds ratios and 95% CIs were calculated. Time to growth was determined by using life-table methods. Data were analyzed by using SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). The funding sources had no role in the design, conduct, or reporting of the study or the decision to publish the manuscript. Results A total of 1009 patients were examined in the Thyroid Nodule Clinic between 1995 and 2000, and 1358 nodules were biopsied. On initial FNA, 854 nodules (in 700 patients) measured 1 cm or greater in maximal diameter with benign cytologic results. Two hundred sixty-eight patients (38%) with 330 benign thyroid nodules (39%) returned for follow-up ultrasonography, with a mean interval of 20 months (range, 1 to 65 months) between examinations (Appendix Figure). The baseline demographic and ultrasonography characteristics of these 268 patients and their nodules were similar to those of the 432 patients who did not return for follow-up (Table 1). Table 1. Demographic and Ultrasonography Characteristics of Patients with a Benign Thyroid Nodule 1 cm in Maximal Diameter Who Returned for Follow-up Ultrasonography as Recommended Compared with Those Who Did Not Change in nodule size over each patients follow-up period was assessed by three methods to facilitate comparison with previous studies. With use of a greater than 50% change in maximal diameter, 14 nodules (4%) were determined to have increased in size upon repeated ultrasonography. With evaluating change in maximal diameter of 3 mm or greater or change in calculated volume (cm3) of 15% or greater, 86 nodules (26%) and 129 nodules (39%), respectively, were determined to have increased in size on follow-up ultrasonography. The time interval between examinations was significantly correlated with nodule growth (r = 0.22; P < 0.001). Table 2 shows mixed-models logistic regression analysis for prediction of thyroid nodule growth (volume change 15%). Time between examinations and lower cystic content remained statistically significant predictors of growth in the final multivariable model. Each year, the background odds of growth increased by 50%. The estimated median time to achieve volume growth of 15% or greater was 35 months (95% CI, 29 to 41 months). The estimated proportion with growth was 53% (CI, 46% to 61%) at 3 years and 89% (CI, 81% to 97%) at 5 years using life-table methods. The patients age, sex, baseline serum TSH concentration, or l-thyroxine use did not predict nodule growth. Table 2. Single-Variable Predictors and Final Multivariable Model To Predict Thyroid Nodule Growth (Volume Increase 15%) Sixty-one patients underwent repeated FNA at the time of the second ultrasonography. The nodules in this group were larger on initial examination (2.7 cm vs. 2.3 cm; P = 0.001) and had increased in volume by an average of 69% during follow-up compared with 14% in those nodules not rebiopsied (P < 0.001). Patient characteristics were similar except for a longer interval between examinations (28 months vs. 18 months) and younger age (43 years vs. 48 years) noted among the rebiopsied group. One of the 74 repeated FNA samples suggested a follicular neoplasm, and the remainder were benign. The nodule was removed; it was a poorly differentiated papillary carcinoma. It had enlarged from 10.1 cm3 to 18.1 cm3 in volume (an 80% increase) over 38 months. Discussion We used ultrasonography to assess the natural history of 330 benign thyroid nodules measuring 1 cm or more in maximal diameter followed for a mean period of 20 months. Although the 268 patients (with 330 nodules) represent only 39% of the benign nodules seen in the Brigham and Womens Hospital Thyroid Nodule Clinic between 1995 and 2000, they appear to be representative of the whole group with respect to demographic and nodule characteristics. Using the most rigorous criteria ( 15% increase in volume), we documented growth in 39% of benign thyroid nodules during follow-up, which indicates that many such nodules grow. Consistent with our findings, Brander and colleagues (10) found that 35% of benign nodules increased in size over 4.9 to 5.6 years. However, the criteria for growth were not defined, and minimal data on repeated FNA were provided (10). Similarly, Papini and colleagues (15) documented an increase in mean nodule volume among patients in the control group of a 5-year randomized study that assessed the efficacy of l-thyroxine suppression therapy for nodular goiter. Our results also support previous conclusions that more cystic nodules are less likely to grow compared with nodules with a greater solid component (5). Current opinion suggests that increasing nodule size has modest but significant power for predicting thyroid cancer (2). Kuma and colleagues found malignancy in 26% of previously unbiopsied nodules that increased in size over a 10- to 30-year period (5). A follow-up study 2 years later reported a malignancy rate of 4.5% among nodules that were previously found to be benign on FNA and subsequently grew (although no definition of growth was provided) (6). In our study, only 1 of 74 rebiopsied nodules was malignant on repeated FNA biopsy. Although only 22% of nodules seen in follow-up were rebiopsied, this group had s

Targeted, High-Depth, Next-Generation Sequencing of Cancer Genes in Formalin-Fixed, Paraffin-Embedded and Fine-Needle Aspiration Tumor Specimens

Implementation of highly sophisticated technologies, such as next-generation sequencing (NGS), into routine clinical practice requires compatibility with common tumor biopsy types, such as formalin-fixed, paraffin-embedded (FFPE) and fine-needle aspiration specimens, and validation metrics for platforms, controls, and data analysis pipelines. In this study, a two-step PCR enrichment workflow was used to assess 540 known cancer-relevant variants in 16 oncogenes for high-depth sequencing in tumor samples on either mature (Illumina GAIIx) or emerging (Ion Torrent PGM) NGS platforms. The results revealed that the background noise of variant detection was elevated approximately twofold in FFPE compared with cell line DNA. Bioinformatic algorithms were optimized to accommodate this background. Variant calls from 38 residual clinical colorectal cancer FFPE specimens and 10 thyroid fine-needle aspiration specimens were compared across multiple cancer genes, resulting in an accuracy of 96.1% (95% CI, 96.1% to 99.3%) compared with Sanger sequencing, and 99.6% (95% CI, 97.9% to 99.9%) compared with an alternative method with an analytical sensitivity of 1% mutation detection. A total of 45 of 48 samples were concordant between NGS platforms across all matched regions, with the three discordant calls each represented at <10% of reads. Consequently, NGS of targeted oncogenes in real-life tumor specimens using distinct platforms addresses unmet needs for unbiased and highly sensitive mutation detection and can accelerate both basic and clinical cancer research.

Genetic and Biological Subgroups of Low-Stage Follicular Thyroid Cancer

Investigations of cancer-specific gene rearrangements have increased our understanding of human neoplasia and led to the use of the rearrangements in pathological diagnosis of blood cell and connective tissue malignancies. Here, we have investigated 3p25 rearrangements of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization. All 11 follicular carcinomas with 3p25 rearrangement exhibited strong, diffuse nuclear immunoreactivity for PPAR gamma, consistent with expression of PPAR gamma fusion protein. Twelve of 42 (29%) low-stage follicular carcinomas had 3p25 aneusomy without PPAR gamma rearrangement (P = 0.01), suggesting that PPAR gamma rearrangement and aneuploidy are independent early events in follicular cancer. Eleven of 12 follicular carcinomas with 3p25 aneusomy exhibited no PPAR gamma immunoreactivity, supporting the existence of two independent pathways. Follicular carcinoma patients with PPAR gamma rearrangement more frequently had vascular invasion (P = 0.01), areas of solid/nested tumor histology (P < 0.001), and previous non-thyroid cancers (P < 0.01) compared with follicular carcinoma patients without PPAR gamma rearrangement. Our experiments identify genetic subgroups of low-stage follicular thyroid cancer and provide evidence that follicular carcinomas with PPAR gamma rearrangement are a distinct biological entity. The findings support a model in which separate genetic alterations initiate distinct pathways of oncogenesis in thyroid carcinoma subtypes.

The Impact of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on Rates of Malignancy for Fine-Needle Aspiration Diagnostic Categories

BACKGROUND Increased recognition of the indolent nature of noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) along with greater insight into the molecular alterations of these tumors has prompted endocrine pathologists to question whether these tumors warrant a diagnosis of carcinoma. However, a change in terminology would affect the rates of malignancy of fine-needle aspiration (FNA) diagnostic categories. Therefore, the aim of this study was to determine the percentage decrease in associated risk of malignancy for each FNA diagnostic category if NFVPTCs were no longer termed carcinomas. METHODS We evaluated a cohort of 655 FNAs with subsequent resection specimens over a 22-month time period. The diagnoses of the preceding FNAs were recorded according to the Bethesda System for Reporting Thyroid Cytopathology. For cases with more than one preceding FNA, the FNA diagnosis associated with the highest risk of malignancy was identified. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify noninvasive tumors. By definition, all of these tumors were encapsulated, partially encapsulated, or well circumscribed and lacked any indication of infiltrative growth, capsular penetration, or lymphovascular invasion. RESULTS Our cohort of 655 FNAs with subsequent resection specimens included 53 (8.1%) nondiagnostic (ND), 167 (25.5%) benign, 97 (14.8%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 88 (13.4%) suspicious for follicular neoplasm (SFN), 94 (14.4%) suspicious for malignancy (SUS), and 156 (23.8%) malignant cases (POS). Surgical resections demonstrated benign findings in 309 (47.2%) and malignant tumors in 346 (52.8%), including 85 NFVPTCs accounting for 24.6% of malignancies. Our rates of malignancy for ND, benign, AUS/FLUS, SFN, SUS, and POS were 18.9%, 13.2%, 39.2%, 45.5%, 87.2%, and 98.7%, respectively. If NFVPTC were no longer termed carcinoma, these rates would drop to 17.0% (10% decrease), 5.4% (59% decrease), 21.6% (45% decrease), 37.5% (18% decrease), 45.7% (48% decrease), and 93.6% (5% decrease), respectively. CONCLUSION Our findings demonstrate that if terminology were changed and NFVPTCs were not considered carcinomas, the rates of malignancy for FNA diagnostic categories would be substantially decreased, with the most clinically significant decrease seen in the SUS category, which demonstrated a relative decrease of nearly 50%.

Multicenter Clinical Experience with the Afirma Gene Expression Classifier

BACKGROUND Increasingly, patients with thyroid nodule cytology labeled atypical (or follicular lesion) of undetermined significance (AUS/FLUS) or follicular neoplasm (FN) undergo diagnostic analysis with the Afirma gene expression classifier (GEC). No long-term, multisite analysis of Afirma GEC performance has yet been performed. METHODS We analyzed all patients who had received Afirma GEC testing at five academic medical centers between 2010 and 2013. Nodule and patient characteristics, fine needle aspiration cytology, Afirma GEC results, and subsequent clinical or surgical follow-up were obtained for 339 patients. Results were analyzed for pooled test performance, impact on clinical care, and site-to-site variation. RESULTS Three hundred thirty-nine patients underwent Afirma GEC testing of cytologically indeterminate nodules (165 AUS/FLUS; 161 FN; 13 suspicious for malignancy) and 174 of 339 (51%) indeterminate nodules were GEC benign, whereas 148 GEC were suspicious (44%). GEC results significantly altered care recommendations, as 4 of 175 GEC benign were recommended for surgery in comparison to 141 of 149 GEC suspicious (P<.01). Of 121 Cyto Indeterminate/GEC Suspicious nodules surgically removed, 53 (44%) were malignant. Variability in site-to-site GEC performance was confirmed, as the proportion of GEC benign varied up to 29% (P=.58), whereas the malignancy rate in nodules cytologically indeterminate/GEC suspicious varied up to 47% (P=.11). Seventy-one of 174 GEC benign nodules had documented clinical follow-up for an average of 8.5 months, in which 1 of 71 nodules proved cancerous. CONCLUSIONS These multicenter, clinical experience data confirm originally published Afirma GEC test performance and demonstrate its substantial impact on clinical care recommendations. Although nonsignificant site-to-site variation exists, such differences should be anticipated by the practicing clinician. Follow-up of GEC benign nodules thus far confirm the clinical utility of this diagnostic test.